Mercapto pyridazinediones

ABSTRACT

4,5-DIMERCAPTO-1,2-DIHYDROPYRIDAZINEDIONES HAVING SUBSTITUENTS ATTACHED TO EACH OF THE NITROGEN ATOMS OF THE PYRIDAZINE NUCLEUS WHICH ARE PREPARED BY TREATING THE CORRESPONDING N,N&#39;&#39;-SUBSTITUTED 4,5-DIHALOPYRIDAZINEDIONE WITH A HYDROSULFIDE. THE SUBSTITUTED 4,5-DIMERCAPTO-1,2DIHYDROPYRIDAZINEDIONES ARE USEFUL AS INHIBITORS OF GASTRIC ACID SECRETION.

United States Patent 3,585,196 MERCAPTO PYRIDAZINEDIONES William A.Bolhofer, Frederick, Pa., assignor to Merck & Co., Inc., Rahway, NJ. NoDrawing. Filed Feb. 1, 1968, Ser. No. 702,182 Int. Cl. C07d 51/04 U.S.Cl. 260-2471 Claims ABSTRACT OF THE DISCLOSURE 4,5 dimercapto 1,2dihydropyridazinediones having substituents attached to each of thenitrogen atoms of the pyridazine nucleus which are prepared by treatingthe corresponding N,N'-substituted 4,S-dihalopyridazinedione with ahydrosulfide. The substituted 4,5-dimercapto-1,2-dihydropyridazinediones are useful as inhibitors of gastric acidsecretion.

BACKGROUND OF THE INVENTION (1) Field of the invention Gastric acidsecretion inhibitors.

SUMMARY OF THE INVENTION This invention is concerned with novelpyridazinedione compounds useful as gastric acid secretion inhibitors.

More specifically, this invention is concerned with 4,5-dimercapto-1,Z-dihydropyridazinediones having substituents attached toeach of the nitrogens of the pyridazine nucleus.

This invention is also concerned with methods for preparing the novelcompounds of this invention which comprises treating the corresponding4,5-dihalopyridazinedione with an alkali hydrosulfide or a compoundcapable of being converted to an alkali hydrosulfide. The invention isconcerned also with pharmaceutical compositions containing the novelpyridazinediones of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS While certain pyridazinedionecompounds are known, particularly those that have been used as dyes,fungicides, and bacteriacides, it has been found that a select group ofheretofore unknown pyridazinedione compounds possess the unique propertyof inhibiting gastric acid secretion in mammals. The preferred productsnow used to control gastric acidity are mainly either anticholinergicagents or antacids. The anticholinergic agents have the disadvantage inthat they act by or through the nervous system by blocking the nerveimpulses to the cells of the gastric mucosa responsible :for secretionof acid. Because of their effect on the nervous system, theanticholinergic agents are non-specific, additionally affecting othersecretory mechanisms of the body as well as other body functionsdependent in Whole or in part on stimulation by the nervous system. Theantacid compounds, on the other hand, have limited effectiveness as theyact only to neutralize the acid after it has been secreted into thestomach, and furthermore, have a very short duration of activity.

The pyridazinedione compounds of this invention do not act by either ofthe above mechanisms and thus afford a new approach to acid inhibitionas they control acid production at the gastric mucosa cellular level.Pharmacological studies indicate that the pyridazinediones of thisinvention effect inhibition at the enzyme level and in addition areeffective in inhibiting histamine stimulated gastric secretion, animportant property not shared with other types of gastric acidinhibitors.

The novel compounds of this invention having this 3,585,196 PatentedJune 15, 1971 property of inhibiting the production of gastric acids canbe illustrated by the structural formula 'ice wherein R and R can be thesame or dissimilar substituents and each represents The loweralkylreferred to in (1) and (2) above advantageously contains from 1-5 carbonatoms. When the loweralkyl radical is substituted as in (2a-m) above, Rand/ or R may be respectively (a) Z-hydroxyethyl or 2 (or 3)-hydroxypropyl (b) 2- (diethylaminoacetoxy) ethyl, 2-(diethylaminoacetoxy) propyl, or 3 (or 4) -(diethylaminoacetoxy)butyl(c) 2-acetoxyethyl or 3-acetoxypropyl, 2-propionyloxyethyl,3-butyryloxypropyl (d) 2-(4-morpholinyl)ethyl (e) 2- 1,1-dioxo-4-thiomorpholinyl) ethyl (f) 3- dimethylamino -2-methylpropy1 2-(dimethylamino ethyl 2- diisopropylamino) ethyl 2-(dibutylamino)ethyl 3(dimethylamino )propyl 3- (diethylamino propyl 2- dimethylamino-2-methylpropyl 3-(dimethylamino)-2,2-dimethylpropyl 2- (diethylaminopropyl 2- (diethylarnino)-1-methylethyl 4- (dimethylamino)-1-methylbutyl(g) carboxymethyl, carboxypropyl (h) phenylethyl, phenylpropyl (i) 2-(piperidino) ethyl or 2- (piperidino)propy1 (j 2-(4-rnethyl-1-piperazinyl) ethyl, 3-(4-methy1-1-piperazinyl)propyl,2-(4-ethyl-1-piperazinyl) ethyl or 2- (4- ethyl-1-piperazinyl)ethyl (k)2- (methylphenylamino)ethyl or 2- (ethylphenyl-amino) ethyl (l)methylbenzylaminoethyl, methylbenzylaminopropyl,

ethylbenzylaminoethyl, or ethylbenzylaminopropyl (m)(l-methyl-3-piperidyl)methyl or (1-ethyl-3-piperidyl methyl (n) 2-(4-thiomorpholinyl) ethyl When the loweralkyl radical is substituted asin (3) above, then R and/ or R may be respectivelyZ-dimethylaminocyclohexyl, 2-diethylaminocyclohexyl or2-ethylmethylaminocyclohexyl. In addition, R and/or R may bechlorophenyl, fluorophenyl, methoxyphenyl, ethoxyphenyl, ordiethylaminophenyl, when the phenyl radical is substituted as in aboveor methylpiperidyl, ethylpiperidyl or propylpiperidyl when the alkylradical is substituted as in (6) above.

While R and R may be the same, it is preferable that when R representsone of the groups stated above, R represents loweralkyl.

The novel compounds of this invention advantageously can be prepared bytreating the corresponding 4,5-dihalopyridazinedione with a compoundcapable of replacing the halogen atoms of the 4,5-dihalo pyridazinedionewith a sulfhydryl group. Compounds which will satisfactorily effect thisreplacement include ammonium hydrosulfide, the alkali metalhydrosulfides such as sodium or potassium hydrosulfide, or sulfides thatmay on hydrolysis be converted to a hydrosulfide such as sodium sulfideor hydrogen sulfide plus an alkali hydroxide.

Although a solvent is not necessary to effect the abovestated reaction,it is deemed desirable for maximum yields. Suitable solvents that may beused to satisfactorily prepare the mercaptopyridazinediones of thisinvention include in addition to the preferred loweralkanols such asethanol, isopropanol, or butanol, the glycols such as ethylene orpropylene.

The temperature at which the reaction is effected is not particularlyimportant, being limited by the boiling point of the solvent employedand the replacement of the halogen atom satisfactorily occurs when thereactants are heated under reflux conditions for about 14 hours, afterwhich time the desired 4,5-dimercapto pyridazinedione may be separatedfrom the reaction mixture by diluting the reaction mixture with waterand then neutralizing it with 6 N hydrochloric acid.

It is obvious to those skilled in the art that the1,2-dihydro-4,5-dimercapto-3,6-pyridazinedione products having a basicamino group in the R and/ or R' substituent may also be obtained as thenon-toxic acid addition salt, such as the hydrochloride, sulfate,phosphate or citrate, as shown in Example 2 below.

EXAMPLE 1 1,2-dicyclohexyl-1,2-dihydro-4,5-dimercapto-3,6-pyridazinedione Sodium hydrosulfide dihydrate (0.92 g., 0.01 mole) and4,5 dihcloro-1,2-dicyclohexyl-l,2-dihydro-3 ,6-pyridazinedione (0.86 g.,0.0025 mole) are dissolved in ml. of ethyl alcohol and the solution isheated under reflux. After two hours the reaction mixture is allowed tocool and the solvent is then removed by concentration under reducedpressure. The residue remaining is then treated by the addition of ml.of water. Acidification of the aqueous mixture with 6 N HCl yields anoily material containing 1,2dicyclohexyl-l,2-dihydro-4,5-dimercapto-3,6-pyridazinedione which afterrecrystallization from absolute alcohol has a M.P. of 162164.5 C.

EXAMPLE 2 1methyl-2-[2-(4-morpholinyl)ethyl]-1,2-dihydro-4,5-dimercapto3,6-pyridazinedioneand its hydrochloride salt 1methyl-2-[2-(4-morpholinyl)ethyl]-l,2-dihydro-4,5-dichloro-3,6-pyridazinedione is treated with sodium hydrosulfide asdescribed in Example 1. After removal of the solvent from the reactionmixture under reduced pressure the residue is mixed with water and madejust faintly acid with 6 N HCl. The 1-methyl-2-[2-(4-morpholinyl)ethyl]- 1,2 dihydro 4,5 dimercapto-3,6-pyridazinedionewhich precipitates is collected and washed with water. Treatment withmethanolic HCl and ether yields the hydrochloride salt which iscrystallized from glacial acetic acid by addition of ether. It has a MP.of l89-191 C.

1-R-2R-4,S-dimercaptopyridazinediones that can be prepared by reactingknown lR-2R-4,5-dihalopyridazinediones with sodium hydrosulfideaccording to the procedure set forth in Examples 1 and 2 are as follows.

Hal SH lis- I Hal 11s Methyl.

Phenyl.

Z-hydroxyethyl; 2-(diethylamino)acetoxyothyl: Z-aeetoxyethyl.

. Methyl.

2-(4-morpholinyD-ethyl. 2-(1,1-dioxo-4thiornorpholinyl)- ethyl.3-(dimethylarnino)-2-metl1ylpropyl: I'Ieptyl. Garboxymcthyl. Cyclohexyl.Phenyl. p-Chlorobenzyl. p-Carboxybeuzyl.

18 do Phenylethyl. 19.... Isopropyl Isopropyl. 20 .do m-Methoxyphenyl:

p-Oarboxyphenyl.

Phenyl.

2-(dimethylamino)ethyl. 2-(diethylamino)etl1yl.2-(diisopropylamino)ethyl.

2-(dibuty11mino)ethyl.

3-(dlmethylamino)propyl. 3-(diethylamino)propyl.Q-(dimethylamino)-2-rnethylpropyl;3-(dirnethylamino)-2,2-din1ethylpropyl; 2-(diethylamlno)-1-methylethyl.2-(diethylamino)-2-methylethyl. 4(dimcthylarnino)-l-methylbutyl.2-(piperidino)ethyl. 2-(4-thiomorpholinyl)ethyl. 2-(l-methyl-l-piperazinyl)cthyl; 3-(4-methyl-l-piperaziuyl)-propyl. 3(4rnorpholinyl)propyl. Z-(rnethylphcnylamino)ethyl.Methylbenzylaminoethyl. Mothylbenzylarninopropyl; 3-(l-mothylpiperidyl).

3-(l-methylplperidyl)methyl. 2-(dimethylamino)cyclohexyl.

2(diethylamino)etl1yl. 2(4-;1orpholinyl)ethyl.

48- p-Fluorophenyl. D0.

49".. m-Methoxyphenyl Do.

50- Isopropyl p-Dimethylaminomethylplionyl.

51 Methyl Methoxycarbonymethyl.

5 Isopropyl 4-(Bfidietpylaminoethoxycarbonyl) p eny The novel compoundsof this invention effectively inhibit acid secretion for a period ofhours. For this reason the mercaptopyridazinedione compounds of thisinvention have special value in the prophylaxis and treatment of pepticulcers. While the preferred dose is a function of the specific compoundused and the individual requirements, generally the compounds of thisinvention are administered in a total daily dose of from about 0.5- 500mg., the preferred dose level being from about l-100 mg. At therecommended doses these compounds have a very favorable therapeuticratio.

As the compounds contemplated within the scope of this invention areeffective upon oral administration, they can be compounded in anysuitable oral dosage form, as in tablet, capsule, suspension, or otherliquid or solid form that can be prepared by procedures well known inthe art. Thus, these novel compounds may be admixed with a suitablediluent such as lactose, and encapsulated; or they may be combined withsuitable binding agents and expanding agents and compressed into tabletform. In addition, a liquid pharmaceutical may be obtained by dissolvingor suspending the novel compounds of this invention in a suitableflavored vehicle. While the compounds are also active upon parenteraladministration, the oral route is generally preferred.

Typical formulations for preparing tablets, capsules, and liquidscontaining the novel mercaptopyridazinediones are described below. Itshould be recognized by one skilled in the art that the formulationsrepresent only one method for making the desired pharmaceuticalcomposition. Factors such as the desired size of the tablet or capsulewill be a determining factor as to the amount of diluent required. Thetype of diluent will be determined by the hardness of the tabletdesired, or whether it is to be made by the wet, dry, or directcompression method. Also to be considered is whether other activeingredients are to be included in the formulation, which may be ofbenefit in controlling hypergastric acidity in a secondary manner, suchas the barbiturates and tranquilizers and the like.

Table containing 25 mg. of 1-R-2R'-4,5- dimercaptopyridazinedione Eachtablet g) 1-R-2; R-4,B-dhnercaptopyridazinedione are Lactose (powder)Ta] 0 Weight of granulation Mix all of the ingredients and then compressinto slugs. The slugs should then be ground to form granules that willpass through a 14-16 mesh screen. The granules may then be re-compressedinto tablets, using a suitable compression mold to form tablets, eachweighing 70 mg.

Capsule containing 50 mg. of 1-R-2-R'-4,5-dimercaptopyrididazinedioneMix the ingrredients so as to evenly distribute the active ingredientthroughout the lactose. Pack the powder into No. 2 empty gelatincapsules. Each capsule should have a net weight of 200 mg.

6 Suspension containing 5 mg. per 5 cc. of l-R-2-R'-4,5-dimercaptopyridazinedione 1,000 ml.

1-R-2-R-4,5-dimercaptopyridazinedione1 gm. Tragacanth30 gm.

Amaranth-10 gm.

Syrup wild cherry U.S.P.600 ml.

Distilled water q.s. ad-l,000 ml.

Hydrate the tragacanth with sufiicient water to form a smooth paste andto this add the 1-R-2-R-4,5-dimercaptopyridazinedione, followed by theAmaranth, which has previously been dissolved in distilled water and thesyrup of wild cherry. The suspension is then brought to a volume of1,000 ml. with distilled water and stirred well to suspend the addedmaterials. Each 5 ml. will contain 5 mg. of1-R-2-R'-4,5-dimercaptopyridazinedione.

What is claimed is:

1. A compound of formula I l-R wherein R represents loweralkyl and Rrepresents loweralkyl or loweralkyl substituted with a 4 morpholinylradical and the non-toxic acid addition salts thereof wherein R containsa 4-morpholiny1 radical.

2. A compound of claim 1 wherein R represents loweralkyl and Rrepresents loweralkyl substituted with a 4-morpholinyl radical.

3. A compound of claim 2 wherein R is methyl and R is2-(4-morpholinyl)ethyl and the nontoxic acid addition salts thereof.

4. A compound of claim 1 wherein R and R represent methyl.

5. A compound of claim 1 wherein R and R represent loweralkyl.

References Cited Wagner and Zook. Synthetic Organic Chemistry, Wiley andSon Inc. New York, 1953, (pp. 778 and 782 relied on).

ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US. Cl.X.R.

